Conjugated linoleic acids (CLAs) refers to a mixture of positional and geometric isomers of linoleic acids, which are unsaturated fatty acids considered essential to the human diet and found preferentially in dairy products and meat. CLAs have generated much interest in the academic and business communities because of their nutritional, therapeutic, and pharmacological properties. There are numerous known CLA compositions, along with various known routes to prepare such compositions. See, e.g., U.S. Pat. Nos. 6,420,577 (Reaney et al.); U.S. Pat. No. 6,015,833 (Saebo et al.); U.S. Pat. No. 6,160,140 (Bhaggan et al.); U.S. Pat. No. 6,034,132 and U.S. Pat. No. 6,019,990 (both to Remmerelt); and U.S. Pat. No. 6,225,486 (Saebo et al.). CLAs have become biologically and commercially important, as they have been observed to inhibit mutagenesis and to provide unique nutritional value.
Typically, CLAs are a mixture of positional isomers of linolelc acid (C18:2) having conjugated double bonds. The cis-9, trans-11 and trans-10, cis-12 isomers are present in greatest abundance in typical CLA compositions, but it is not absolutely certain which isomers are responsible for the biological and heightened nutritional activity observed. It has been noted from labeled uptake studies that the 9,11 isomer appears to be somewhat preferentially taken up and incorporated into the phospholipid fraction of animal tissues, and to a lesser extent the 10,12 isomer. (See Ha et al., Cancer Res., 50:1097 (1991)).
The properties of unsaturated fatty acids and their derivatives can be altered by rearrangement, i.e., isomerization, of the structure of the double bond, either with respect to the steric position or the position in the carbon chain of the molecule of the fatty acid. As noted above, conjugated fatty acid derivatives are of great technical and commercial interest and, therefore, many attempts have been made to isomerize unconjugated fatty acids to conjugated ones. Without being bound by any particular theory, it is believed that such a shifting of the double bond is possible because the conjugated form has a lower state of energy than the unconjugated form.
Previously known routes to produce conjugated unsaturated compounds include hydrogenation of fats using a variety of catalysts. These routes, however, often lead to incomplete isomerization and unwanted side reactions, such as polymerization and intramolecular cyclization. Other known routes include isomerization with an excess of alkali metal hydroxide in an aqueous or alcoholic medium, which leads to a quantitative isomerization. However, this route suffers from the limitation that a considerable excess of alkali metal hydroxide must be used, so that the conjugated fatty acids or fatty acid compounds are obtained in the form of their alkali soaps and have to be recovered and isolated accordingly. These techniques differ in the use of a particular solvent, temperature and pressure. See, e.g., U.S. Pat. No. 3,162,658 (Baltes et al.).
The rearrangement of the double bonds of linoleic acids to conjugated positions has been shown to occur during treatment with catalysts such as nickel or alkali at high temperatures, and during auto oxidation. Theoretically, eight possible geometric isomers of 9,11 and 10,12 octadecadienoic acid (c9, c11; c9, t11; t9, c11; t9, t11; c10, c12; c10, t12; t10, c12 and t10, t12) would result from the isomerization of c9, c12-octadecadienoic acid. Again, without being bound by any particular theory, a general mechanism for the isomerization of linoleic acids has been described by J. C. Cowan in JOACS 72:492-99 (1950). The formation of certain isomers of CLAs is thermodynamically favored as described therein. The relatively higher distribution of 9,11 and 10,12 isomers apparently results from the further stabilization of the c9, t11 or t10, c12 geometric isomers.
U.S. Pat. No. 6,420,577 (Reaney et al.) describes a process for making CLAs by reacting a linoleic acid-rich oil with a base, in the presence of a catalytic amount of such a base, in an aqueous medium via simultaneous saponification and quantitative isomerization. However, this process utilizes a heightened temperature (>170° C.). Higher temperatures lead to the formation of undesirable CLA isomers, including the trans, trans-CLA isomers.
U.S. Pat. No. 6,160,140 (the '140 patent), claims the conversation of a linoleic acid-containing oil, free fatty acid or alkyl ester to CLAs by treating it with a base in an alcohol solution, where the alcohol has at least 3 carbons and at least 2 hydroxyl groups. The preferred embodiment of the '140 patent is to use potassium hydroxide in propylene glycol. The use of solvent in the conjugation (isomerization) step gives rise to the potential formation of unwanted CLA-alcohol esters (e.g., CLA-propylene glycol esters).
U.S. Pat. No. 3,162,658 (the '658 patent), describes the use of alkali metal hydrocarbyl alcoholates or alkali metal amides to isomerize esters of unconjugated polyethylene acids such as linoleic acids. But it uses polar solvents for the isomerization step, which is undesirable. The '658 patent also makes no mention of converting the resultant conjugated esters to the corresponding acids.
U.S. Pat. No. 3,984,444 (Ritz et al., the '444 patent), describes the isomerization of an ester of an alcohol having 1 to 12 carbon atoms and a fatty acid having 10 to 24 carbon atoms and isolated double bonds to the corresponding compound having conjugated double bonds using alkaline metal alcoholates in strongly polar aprotic solvents. As noted above, the use of solvents in the conjugation step is undesirable. The '444 patent does not teach how to convert the resultant conjugated esters to the corresponding acids as well.
Typical procedures for the conversation of fatty acid methyl esters (FAME) to fatty acids (FA), such as those described in U.S. Pat. Nos. 4,185,027 and 5,872,289, involve the use of acidic catalysts. The use of such acidic catalysts is undesirable.
WO 01/14304 uses steam in the presence of a catalyst to directly hydrolyze FAME to FA. The reaction is carried out at a heightened temperature, which leads to the formation of undesirable CLA isomers, including the trans, trans-CLA isomers. Similarly, WO 97/07187 uses near critical temperatures and supercritical pressures to accomplish the transformation of FAME to FA.
GB 1589314 uses alkali metal hydroxides in alkyl nitrile solution for the conversation of FAME to FA.
U.S. Pat. Nos. 5,892,074 and 6,153,774 describe a process for making CLA enriched in the c9, t11 isomer from methyl ricinoleate by forming mesylate or tosylate esters at the 12 hydroxy position and reacting the diester with a strong organic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The sulfonyl halides used as the derivatizing agent, however, liberate corrosive hydrogen halides that must be scrubbed from the process effluent gas and neutralized. In addition, the organic byproduct resulting from treatment with the organic base is an organic amine salt of a sulfonic acid which must be completely removed if the CLA is to be used as a food supplement. Further, the organic base used is a fairly expensive organic amine.
PCT Application No. WO 118161 A2 discloses a process similar to that disclosed in U.S. Pat. Nos. 5,892,074 and 6,153,774, but uses castor oil instead of methyl ricinoleate as a starting component. The process suffers from the same drawbacks outlined above using methyl ricinoleate as a starting component. In addition, the process treats the tosylate or mesylate compounds with a mineral acid, which further complicates the recovery of material from the process.
Chemistry and Physics of Lipids, 2002, 119, 23-31 describes the use of potassium hydroxide to cause the elimination of the mesylate ester of methyl ricinoleate. This process also suffers from the same drawbacks that come with the use of a sulfonyl halide.
There exists a need for an improved process to produce CLA which is enriched with the highly desired c9, t11 isomer. Additionally, there is a need for an improved process to readily and economically produce such CLA compositions in a safer and more environmentally friendly way.